Finasteride, marketed under the tradename of PROSCAR.RTM., by Merck & Co., Inc. is 17.beta.-(N-tert-butyl carbamoyl)-4-aza-5.alpha.-androst-1-en-3-one and is a 5.alpha.-reductase inhibitor for use in treating acne, female hirsutism, and particularly benign prostatic hyperplasia. See U.S. Pat. No. 4,760,071 (1988), the entire disclosure of which is incorporated herein by reference.
The synthesis of finasteride in U.S. Pat. No. 4,760,071 involves reacting the 17.beta.-(2-pyridylthio) carboxylate of 4-aza-5.alpha.-androst-1-ene-3-one with t-butylamine. A further synthesis of finasteride is described in Synthetic Communications, 30 (17), p. 2683-2690 (1990), the entire disclosure of which is incorporated herein by reference, including the reacting of the 17-acylimidazole of 4-aza-5.alpha.-androst-1-en-3-one with t-butylanine.
However, both of these reactions require the use of heterocyclic aromatic amines which are expensive and give rise to environmental safety and toxicity considerations. Both of these intermediates are prepared from the 17.beta.-carboxylic acid.
The Bodroux reaction, described by F. Bodroux in the references, Bull. Soc. Chim. France 33, 831 (1905); 35, 519 (1906); 1, 912 (1907); Compt. Rend. 138, 1427 (1904); 140, 1108 (1905); 142, 401 (1906) discloses the reaction of the magnesium halide salts of amines with esters. However, there is no description or teaching that the reaction can be applied to the reaction of a sterically hindered amine, e.g. t-butyl amine, with a sterically hindered ester such as 1.
What is desired in the art is a method of synthesis of finasteride, which is environmentally safe and non-toxic, and does not utilize an aromatic heterocyclic amine. Preferably, the starting compound could be the 17-beta ester, (1) which would eliminate one step of the process in producing the above heterocyclic intermediates.